1. Field of the Invention
This invention describes a hitherto unknown and therefore new class of compounds which are analogues of 1xcex1,25-(OH)2D3 and show selective activity on cell functions.
2. Description of Related Art
General Introduction
Vitamin D of either nutritional (vitamin D2 or D3) origin or produced in the skin under the influence of ultraviolet light is metabolized in several tissues to produce firstly 25-hydroxyvitamin D3 [25-OHD3] and later 1xcex1,25-dihydroxyvitamin D3 [1xcex1,25-(OH)2D3] and numerous other vitamin D metabolites (1-6). Several hydroxylases present in different tissues (e.g. liver, kidney, placenta, keratinocytes, fibroblasts, monocytes, lymphocytes, bone cells . . . ) are responsible for both the activating and inactivating pathways of the parent vitamin D molecules. 1xcex1,25-(OH)2D3 behaves as a classical steroid hormone as its synthesis is feedback controlled by several hormones, ions and humoral factors to maintain a normal body homeostasis of plasma and bone minerals. Moreover the vitamin D hormone(s) act via binding and activation of specific vitamin D receptors, present in most tissues and cells. The steroid-receptor complex then functions as a transactivating factor by binding to specific DNA sequences known as vitamin D responsive elements so that transcription of numerous genes is either activated or inactivated (7,8). This gene (in)activation occurs in collaboration with other nuclear accessory factor(s) of which the vitamin A receptor (RXR) is part of (9,10). Moreover there is some evidence for the activity of vitamin D, its metabolites and analogues to act via nongenomic mechanisms, either by activating calcium channels or other membrane or second messenger signals (11-13). Vitamin D, its metabolites and analogues have potent effects on calcium and phosphate metabolism, and therefore they can be used for prevention and therapy of vitamin D deficiency and other disorders of plasma and bone mineral homeostasis (e.g. osteomalacia, osteoporosis, renal osteodystrophy, disorders of the parathyroid function). Moreover vitamin D receptors are found in numerous tissues and cells that do not belong to the target tissues responsible for the just mentioned calcium homeostasis. Such cells include most cells belonging to the endocrine system and vitamin D, its metabolites and analogues are capable of influencing the hormonal secretion of these glands or tissues (e.g. insulin, parathyroid, calcitonin, pituitary hormones). Vitamin D receptors and vitamin D activity have also been documented in calcium transporting tissues other than the intestine and bone (e.g. placenta and mammary glands). In addition vitamin D receptors and vitamin D action have been observed in most other cells (e.g. cells belonging to the immune system, skin cells). These cells or tissues can be of a benign, adenomatous or of a malignant type. These so-called noncalcemic effects of vitamin D, its metabolites and analogues create the possibility to use such compounds for various therapeutic applications such as modification of the immune system, modification of hormone secretion, altering calcium transport in several tissues, modification of intracellular calcium concentration, induction of cell differentiation or inhibition of cell proliferation (14,15). In particular such compounds may be useful in the therapy of disorders characterized by increased cell proliferation (e.g. psoriasis, cancer) (16-18).
To increase the therapeutic potential of the natural vitamin D hormone(s), analogues can be synthesized with increased potency for a specific action and reduction of another type of action. For example to obtain an anti-psoriasis drug analogues can be synthesized with an increased activity on keratinocytes and lymphocytes present in the affected skin areas but with decreased effects on serum, urinary or bone calcium (19-23). Similarly analogues can have an increased potency to inhibit proliferation of cancer cells (e.g. leukemia or breast cancer cells) and/or increase the differentiation of such cells, either alone by their intrinsic potency or enhance such effects in combination with other drugs (e.g. growth factors or cytokines, other steroid or antisteroid hormones or retinoic acids or related compounds) and at the same time have a reduced potency to influence serum, urinary or bone calcium or phosphate homeostasis. Another such example would be analogues with increased activity on specific hormone secretion (e.g. parathyroid hormone, insulin) without the same relative potency for the other activities of the natural vitamin D hormone(s). Analogues with increased activity on non-malignant cells belonging to the immune system could be used for the treatment of immune disorders (e.g. autoimmnune disorders, AIDS, prevention of graft rejection or graft versus host reaction) especially if their effect on other systems (e.g. calcium and phosphate metabolism) would be relatively weakened. Moreover analogues can be developed with increased activity on bone forming cells without a simultaneous potency on bone resorbing cells or vice versa and such analogues could be useful in the treatment of bone disorders.
A number of vitamin D analogues with modifications in the specific action in different tissues (especially the potency ratio on cell differentiation and calcemic effects) have been described previously with variable success in such differentiation. Especially oxa analogues in the side chain (patent WO 90/09992; EP 0385 446A 2), modifications or homologation of the side chain (WO 87/00834, international patent classification CO7C 172/00), changes in the stereochemistry at carbon 20 (WO 90/09991, international patent classification CO7C 401/00, A61K 31/59), modifications on C11 of the C ring (EP 89/401,262-4) and epoxy analogues (PCT/EP 92/0126) of the side chain displayed interesting characteristics.
Present Invention
The present invention relates to the synthesis and biological evaluation of original compounds which still maintain some of the essential characteristics of vitamin D action but with a more selective pattern, (i.e. not all the actions of the physiological vitamin D hormone are maintained with the same relative potency) and with a structure that can be thoroughly modified in the central part. Indeed within the structure of vitamin D one may distinguish three different parts : (i) a central part consisting of the bicyclic CD-ring system; (ii) an upper part, consisting of the side-chain which is connected to position 17 of the D-ring; (iii) a lower part, consisting of the A-ring and the xcex94(5,7)-diene (the so-called seco B-ring), which is connected to position 8 of the C-ring. One aim of the present invention is to bring about substantial structural modifications in the central part of vitamin D. 
In particular the present invention relates to analogues of vitamin D, which lack the combined presence of the trans-fused six-membered C-ring and of five-membered D-ring, but still possess a central part consisting of a substituted chain of five atoms, atoms which correspond to positions 8, 14, 13, 17 and 20 of vitamin D, and at the ends of which are connected, at position 20 a structural moiety representing part of the side-chain of vitamin D or of an analogue of vitamin D, and at position 8 the xcex94(5,7)-diene moiety connected to the A-ring of the active 1-alpha-hydroxy metabolite or of an established vitamin D analogue.